Renin is one of the enzymatic components of the renin-angiotensin system illustrated hereinafter, the products of which perform physiologically important roles in maintaining cardiovascular homeostasis and contribute to the increase in arterial pressure in various hypertensive states [S. Oparil and E. Haber, New England J. Med. 291, 389 (1974); W. S. Peart, New England J. Med. 292, 302 (1975); E. Haber et al., Clin. Sci. Mol. Med. 48, 49 s (1975); J. O. Davis, Clin. Sci. Mol. Med. 48, 30 (1975)]. ##STR2##
Renin, produced and released by the kidney juxtaglomerular cells, reacts with the renin substrate (angiotensinogen) to produce angiotensin I, an inactive decapeptide, which itself is converted, mainly in the lung, to angiotensin II by the angiotensin converting enzyme (ACE).
Angiotensin II is the most powerful endogenous substance of pressor action which has been known up to the present time, and participates in regulating the release of renin by means of a direct feedback mechanism.
The renin-angiotensin system also constitutes one of the main mechanisms for controlling the secretion of aldosterone from the suprarenal cortex, and the release of aldosterone is known to determine retention of Na.sup.+, fluids and caliuresis.
Compounds which are inhibitors of the renin-angiotensin system are currently used for treating hypertension.
Said compounds have the drawback of producing side effects such as the onset of compensatory hyperreninemia.
Moreover, recent experimental studies have shown that renin is present and is synthesized in the vascular smooth musculature, and could therefore play a not insignificant role im maintaining blood pressure. It has therefore been considered opportune to research the field of specific renin inhibitors for treating hypertension.
Said inhibitors pertain to the following three classes:
(1) pepstatin and analogues PA1 (2) lipids and phospholipids PA1 (3) renin substrate analogues
However, pepstatin and analogues are very effective in reducing blood pressure only in animal hypertension models (I.sub.50 0.1 .mu.M), are ineffective in normotensive rats, and also have poor inhibition specificity, in that they act not only on renin but also on other acid proteases such as pepsin, isorenins and cathepsin D. The anti-hypertensive activity of lipids and phospholipids, which has been repeatedly observed in vitro, has recently been questioned, as has their importance as physiological regulators of the renin-angiotensin system. [M. J. Antonaccio and D. W. Cushman, Federation Proc., 40, 2275 (1981)].
Much interest has however been aroused by the compounds of the third class, the synthetic peptide inhibitors, in the form of structural analogues of renin substrate fragments incorporating the bonds Leu.sup.10 --Leu.sup.11 and Leu.sup.10 --Val.sup.11 hydrolysed by renin. Said compounds are very potent inhibitors (I.sub.50 from 5.9 .mu.M to 10 .mu.M) and are highly specific. [J. Burton et al., Proc. Acad. Sci. U.S.A., 77, 5476 (1980); M. Szelke et al., European Patent Application No. 0-045-665, (1982); M. Szelke et al., Nature, 299, 555 (1982)]. Of these, the octapeptide His--Pro--Phe--His--Leu--Val--Ile--His and the decapeptide Pro--His--Pro--Phe--His--Leu--Val--Ile--His--Lys of the N-terminal sequence of human angiotensinogen, in which the hydrolysable Leu--Val bond has been reduced to --CH.sub.2 --NH-- in order to block hydrolysis by the renin, and the decapeptide Pro--His--Pro--Phe--His--Phe--Phe--Val--Tyr--Lys of the N-terminal sequence of equine angiotensinogen has been synthesised.
However, this latter decapeptide, which is a specific inhibitor of human renin in vitro and an effective in vivo antihypertensive, has a very short action duration (about 4 minutes) and this represents a limitation to its clinical application (J. Burton, U.S. Pat. No. 4,269,827).